Our proposal, Enduring Effects of Early-Life Serotonin Signaling, explores the hypothesis that tight control of developmental determinants of serotonin (5-HT) signaling is required to achieve normal patterns of behavioral flexibility and to minimize risk for life-long neuropsychiatric disorders. To test our hypothesis, and to identify opportunities for reversal of disrupted early-life 5-HT signaling, we assemble a highly collaborative team of leading neuroscientists with experience in the development and molecular plasticity of 5-HT signaling. In Project 1, Evan Deneris tackles the support that CNS-synthesized 5-HT signaling plays in the elaboration of raphe neuron gene expression that can support stress-modulated, epigenetic programming. In Project 2, Pat Levitt builds upon his group's discovery of the placenta as a major source of forebrain 5-HT during embryonic development, Levitt's efforts assess how placental-specific disruption of 5-HT synthesis and metabolism leads to enduring effects on brain development and function and whether alterations are reversible. In Project 3, Randy Blakely elucidates the molecular and functional consequences, and potential for reversal, of an autism-associated 5-HT transporter (SERT) mutation (SERT Ala56), and how both either/or CNS and peripheral sites of expression contribute to life-long behavioral deficits, while developing novel conditional SERT mutation expression models. In Project 4, Ron Emeson brings his group's advanced understanding in 5HT2c receptor expression and signaling to bear on the timing and regional specificity of stress-dependent 5HT2c editing, elucidating their mechanisms, biochemical and behavioral consequences and possibilities for reversal. Finally, Mark Wallace leads novel education and outreach programs, extending ARRA-funded efforts to enhance community understanding of neuroscience research and mental illness and that train young scientists in the research and outreach missions of the Conte Center.